PROJECT SUMMARY We propose a Randomized Clinical Trial (RCT) to compare outcomes in patients with major depressive disorder (MDD) treated according to the patient's CYP2D6 genotype status versus empiric standard-of- care psychotropic therapy. We hypothesize that CYP2D6 genotype and predicted functional status of the CYP2D6 enzyme with medication alerts suited to the patient's innate drug metabolism will refine psychotropic medication selection and decrease both psychiatric hospital length of stay and re-admission. The trial setting is Hartford Hospital, which offers 2 key institutional resources: the Institute of Living (IOL) and the Genetics Research Center (GRC). The IOL is a major research-based psychiatric hospital with a national reputation for excellence, comprehensive patient care, research and education in the fields of behavioral, psychiatric and addiction disorders. The IOL has developed and implemented the Clinical Evaluation and Monitoring System (CEMS), an innovative electronic messaging system that transmits clinically actionable guidance to the physician on hospitalized patients, and which will be utilized here as an efficient, rapid way to advance genotype information to clinicians. The GRC, led by the PI, Dr. G. Ruao, has served as incubator for a Medicare-certified and State-licensed pharmacogenetic clinical laboratory and consultation, to which nearly 4000 patients have been referred since 2005. IOL and GRC have published and presented pharmacogenetic data and a pilot clinical study supporting the rationale for the RCT. In the RCT, this 5-year R01 Program will assign 500 patients to standard therapy (Group S) for whom CYP2D6 genetic information is determined but not transmitted to the treating clinician and psychotropic therapy is empirically determined, and 1000 to genetically guided therapy (Group G) where genotyping result and treatment recommendations are furnished via CEMS to the clinician within 24 hours of admission. CYP2D6 genotyping will consist of testing for all polymorphisms that result in an enzyme with sub-normal or supra-normal function. For the 40% of patients in Group G who are poor or rapid metabolizers, medications primarily metabolized by the CYP2D6 enzyme are proscribed. The primary endpoint is hospital length of stay and the secondary endpoint, the frequency of 30 day hospital readmission. Additional research based on genetic stratification of both Group S and Group G will investigate specific psychotropic usage. The Program is anchored by the high inpatient census and CEMS system at IOL, developed by this Program's lead clinician, Dr. J.W. Goethe. Dr. T.R. Holford (Yale) will serve as a statistical consultant and Dr. D. Flockhart (Indiana) will serve as a medical consultant. The expected benefits are quantitative understanding of the effect of providing CYP2D6 pharmacogenetic information on outcomes and associated costs and objective benchmarking for the comparative effectiveness of CYP2D6 genotyping for guiding psychotropic therapy.